Quinolinium conjugates of cyclosporin

Abstract

The present invention relates to conjugates of cyclosporin with quinolium mitochondrial targeting groups, and their therapeutic uses.

The invention claimed is: 
     
       1. A cyclosporin conjugate which is a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       in which:
 A represents 
 
       
         
           
           
               
               
           
         
         B represents methyl or ethyl, 
         R 2  represents ethyl or isopropyl, 
         R 4  represents —CH 2 CH(CH 3 )CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH(CH 3 )CH 3  or —CH(CH 3 )CH 2 CH 3 , 
         either (a) one of R 1  and R 1 * represents -L 1 Z 1  and the other represents hydrogen, and R 3  represents hydrogen, C 1 -C 3  alkyl or C 2 -C 4  alkenyl, (b) one of R 1  and R 1 * represents methyl and the other represents hydrogen, and R 3  represents -L 3 Z 3 , or (c) one of R 1  and R 1 * represents -L 1 Z 1  and the other represents hydrogen, and R 3  represents -L 3 Z 3 , 
         L 1  and L 3  independently represent a C 1 -C 6  alkylene moiety, a C 2 -C 6  alkenylene moiety or a —(CH 2 CH 2 O) n (CH 2 ) m — moiety in which n represents 1 to 3 and m represents 0 to 2, and 
         Z 1  and Z 3  independently represent a moiety of formula (II*): 
       
       
         
           
           
               
               
           
         
         in which Q 1 * to Q 7 * independently represent a hydrogen atom, a C 1 -C 6  haloalkyl group, a —OR′ group, or a —NR′R″ group, wherein R′ and R″ are the same or different and represent hydrogen or a C 1 -C 6  alkyl group, and wherein four to seven of Q 1 * to Q 7 * represent hydrogen. 
       
     
     
       2. The conjugate according to  claim 1 , in which A represents 
       
         
           
           
               
               
           
         
       
       B represents methyl, R 2  represents ethyl and R 4  represents —CH 2 CH(CH 3 )CH 3 . 
     
     
       3. The conjugate according to  claim 1 , in which R 1  represents -L 1 Z 1 , R 1 * represents hydrogen and R 3  represents hydrogen, C 1 -C 3  alkyl or C 2 -C 4  alkenyl. 
     
     
       4. The conjugate according to  claim 3 , in which L 1  represents, a C 1 -C 6  alkylene moiety. 
     
     
       5. The conjugate according to  claim 1 , in which R 1  represents methyl, R 1 * represents hydrogen and R 3  represents -L 3 Z 3 . 
     
     
       6. The conjugate according to  claim 5 , in which L 3  represents a C 2 -C 6  alkenylene moiety. 
     
     
       7. The conjugate according to  claim 1 , in which Z 1  and Z 3  independently represent a moiety of formula (II*a), (II*b) or (II*c): 
       
         
           
           
               
               
           
         
       
     
     
       8. A pharmaceutical composition comprising a cyclosporin conjugate which is a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       in which:
 A represents 
 
       
         
           
           
               
               
           
         
         B represents methyl or ethyl, 
         R 2  represents ethyl or isopropyl, 
         R 4  represents —CH 2 CH(CH 3 )CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH(CH 3 )CH 3  or —CH(CH 3 )CH 2 CH 3 , 
         either (a) one of R 1  and R 1 * represents -L 1 Z 1  and the other represents hydrogen, and R 3  represents hydrogen, C 1 -C 3  alkyl or C 2 -C 4  alkenyl, (b) one of R 1  and R 1 * represents methyl and the other represents hydrogen, and R 3  represents -L 3 Z 3 , or (c) one of R 1  and R 1 * represents -L 1 Z 1  and the other represents hydrogen, and R 3  represents -L 3 Z 3 , 
         L 1  and L 3  independently represent a C 1 -C 6  alkylene moiety, a C 2 -C 6  alkenylene moiety or a —(CH 2 CH 2 O) n (CH 2 ) m — moiety in which n represents 1 to 3 and m represents 0 to 2, and 
         Z 1  and Z 3  independently represent a moiety of formula (II*): 
       
       
         
           
           
               
               
           
         
         in which Q 1 * to Q 7 * independently represent a hydrogen atom, a C 1 -C 6  haloalkyl group, a —OR′ group, or a —NR′R″ group, wherein R′ and R″ are the same or different and represent hydrogen or a C 1 -C 6  alkyl group, and wherein four to seven of Q 1 * to Q 7 * represent hydrogen, 
       
       and a pharmaceutically acceptable excipient, diluent or carrier. 
     
     
       9. A method of treating a patient suffering from or susceptible to disease or disorder susceptible to amelioration by inhibition of cyclophilin D, which method comprises administering to said patient a cyclosporin conjugate which is a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       in which:
 A represents 
 
       
         
           
           
               
               
           
         
         B represents methyl or ethyl, 
         R 2  represents ethyl or isopropyl, 
         R 4  represents —CH 2 CH(CH 3 )CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —CH(CH 3 )CH 3  or —CH(CH 3 )CH 2 CH 3 , 
         either (a) one or R 1  and R 1 * represents -L 1 Z 1  and the other represents hydrogen, and R 3  represents hydrogen, C 1 -C 3  alkyl or C 2 -C 4  alkenyl, or (b) one of R 1  and R 1 * represents methyl and the other represents hydrogen, and R 3  represents -L 3 Z 3 , or (c) one or R 1  and R 1 * represents -L 1 Z 1  and the other represents hydrogen, and R 3  represents -L 3 Z 3 , 
         L 1  and L 3  independently represent a C 1 -C 6  alkylene moiety, a C 2 -C 6  alkenylene moiety or a —(CH 2 CH 2 O) n (CH 2 ) m — moiety in which n represents 1 to 3 and m represents 0 to 2, and 
         Z 1  and Z 3  independently represent a quinolium ring which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a C 1 -C 6  alkyl group, a C 1 -C 6  haloalkyl group, a —OR′ group, a —COOR′ group, a —CONR′R″ group and a —NR′R″ group, wherein R′ and R″ are the same or different and represent hydrogen or a C 1 -C 6  alkyl group. 
       
     
     
       10. The method according to  claim 9 , wherein said disease or disorder is ischaemia/reperfusion injury or neurodegenerative disease.